1. The Field of the Invention
This invention is in the field of photoprotection of human skin. More particularly, the invention relates to compositions and methods for this use by topical application to reduce if not eliminate the inhibition of collagen synthesis in human skin after incidental and/or direct exposure to UV radiation as would occur daily, and as would occur after recreational exposure to UV radiation during a planned, extended period in the sun.
2. The State of the Art.
Human skin is a complex organ which extends over the entire body. There are different types of skin at different portions of the body; for example, facial skin is different from that of the scalp, and even the skin on the front (palm) of the hand is different than that on the back of the hand. Although the type of skin can vary over a person's body, skin is generally composed of two main layers of tissue. The epidermis, the outermost layer, is composed of several layers. The dermis, corium, or cutis vera, the true skin, is composed of a papillary layer above and a reticular layer below.
As far as mammals go, humans are essentially hairless; that is, most of the skin of the human body can be seen without interference from hair. The skin is thus exposed to whatever insults (natural and man-made) the environment harbors. Since it was first understood that the sun caused erythema, people have taken measures to avoid its “harmful rays.” There is a difference between the physiology of chronologically-aged or intrinsically-aged skin (old skin) in comparison with that of photoaged skin. Old skin typically maintains a smooth and unblemished appearance, in comparison with the leathery, blotchy, and often fine and deep wrinkling of photoaged skin. The epidermis of old skin is typically thinner than normal, whereas that of photoaged aged skin can often be thicker than normal (acanthotic) and then atrophies over time. See also N. A. Fenske and C. W. Lober, “Structural and functional changes of normal aging skin,” J. Am. Acad. Dermatol., 15:571–585 (1986).
Photoaging is a term presently used to describe the changes in appearance and/or function of human skin as a result of repeated exposure to sunlight, and especially in reference to wrinkles and other changes in the appearance of the skin thought to be related to exposure to the sun. The ultraviolet (UV) component of sunlight, particularly UVA and UVB, is generally believed to be the principal causative agent in photoaging. The extent of UV exposure required to cause “photoaging” is not currently known, although the amount sufficient to cause erythema (reddening, commonly seen as sunburn) in human skin is quantified empirically as the “minimal erythemal dose” (“MED”) from a given UV source. Repeated exposure to sunlight UV at levels that cause erythema and tanning are, nevertheless, commonly associated with photoaging.
Solar radiation reaching the earth's surface that effects and enables various animals, including humans, comprises ultraviolet (UV) (λ<400 nm), visible (400 nm<λ<700 nm), and infrared (IR) (λ>700 nm). UV radiation is generally divided into UVA (320–400 nm), UVB (290–320 nm), and UVC (<290 nm); UVC radiation is blocked from reaching the earth's surface by stratospheric ozone. UVB doses in the range of 30–50 mJ/cm2 skin cause erythema in most fair-skinned people. Sunlight reaching the surface of the earth when the sun is essentially overhead provides the following amounts of radiation: 0.5% UVB; 6.5% UVA; 38.9% visible light; and 54.0% IR. These radiation types provide the following energy fluxes: 2.11 mJ/cm2·s (21.1 W/m2) for UVB; 8.57 mJ/cm2·s (85.7 W/m2) for UVA; 53.2 mJ/cm2·s (532 W/m2) for visible light; and 72.2 mJ/cm2·s (722 W/m2) for IR.
Photoaging is characterized clinically by coarseness, wrinkles, mottled pigmentation, sallowness, laxity, telangiectasia, lentigines, purpura and relative ease of bruising, atrophy, depigmented areas, eventually premalignant, and ultimately malignant neoplasms. Photoaging commonly occurs in skin that is habitually exposed to sunlight such as the face, ears, bald areas of the scalp, neck, forearms, and hands.
Sunscreens are commonly used to prevent sunburn (erythema) of skin areas that are exposed to sunlight. Sunscreens are topical preparations that contain ingredients that absorb, reflect, and/or scatter UV light. Some sunscreens are based on opaque particulate materials, among them zinc oxide, titanium oxide, clays, and ferric chloride. Because such preparations are visible and occlusive, many people consider these opaque formulations cosmetically unacceptable. Other sunscreens contain chemicals such as p-aminobenzoic acid (PABA), oxybenzone, dioxybenzone, ethylhexyl-methoxy cinnamate, octocrylene, octyl methoxycinnamate, and butylmethoxydibenzoylmethane that are transparent or translucent on the skin. While these types of sunscreens may be more acceptable cosmetically, they are still relatively short-lived and susceptible to being removed by washing or perspiration.
As noted above, the generally accepted etiology of photodamage to skin involves an exposure to sunlight sufficient to cause erythema (sunburn or reddening; literally a flush upon the skin), and it is now known that sufficient UV radiation causes erythema. This philosophy dictates that present compositions and methods for inhibiting photoaging include the use of compounds that block or absorb UV, and that such compositions need be used only when there is a sufficient likelihood that exposure to sunlight will result in erythema. More recent sunscreen compositions include combinations of compounds that block both UVA and UVB radiation.
According to Physiology, Biochemistry, and Molecular Biology of the Skin, 2nd Ed., ed. by L. A. Goldsmith (New York: Oxford Univ. Press, 1991), UVA is considered both melanogenic and erythemogenic and UVA exposure induces synthesis of a 32 kDa stress protein in cultured fibroblasts. This text further describes that after a latent period of several hours after UV irradiation erythema becomes apparent (i.e., “delayed” erythema); “immediate” erythema is described as usually not apparent after UVB or UVC exposures but does occur, in a dose-dependent manner, after exposure to UVA. Goldsmith teaches that 250–290 nm (UVC region) is considered to be the most erythemogenic radiation with one thousand-fold less erythema at 290–340 nm (UVB and UVA1 region); erythema from UVB/C is taught to be a function of the total radiation exposure rather the intensity of the radiation exposure.
Retinoids have been used to retard the effects of photoaging in skin appearing to have been damaged by exposure to the sun. U.S. Pat. No. 4,877,805 describes the treatment of photoaged skin after photoaging has become apparent clinically. This patent indicates there is little point in beginning the application of a retinoid to treat photodamaged skin until the effects of photoaging begin to appear.
On the other hand, our patent applications (based on copending U.S. patent application Ser. No. 08/588,771, filed Jan. 19, 1996, and provisional application 60/048,520, filed Jun. 4, 1997, and 60/057,976, filed Sep. 5, 1997, all related to photoaging of human skin, the disclosures of which are incorporated herein by reference for all purposes) describe the damage matrix metalloproteinases (MMPs) do to skin, that their activity is greatly enhanced after exposure to UV radiation, and that photoaging can and should be treated prior to the unambiguous clinical appearance of photoaging. These patent applications describe treatment of photoaged skin (i.e., skin that has been exposed to solar UV radiation, regardless of whether erythema or the clinical signs of photoaging are apparent) by the topical administration of inhibitors of MMPs (i.e., direct inhibitors of the proteinase) and of transcription factors (e.g., inhibitors of AP-1) that affect MMP expression.
In view of the foregoing, it can be argued that the art adheres presently to the philosophy that sunlight, especially UV radiation, causes erythema, and that repeated episodes of erythema and similarly chronic exposure to the sun result in photoaged skin. This philosophy is based on the observation that people who have spent significant amounts of time in the sun have skin that appears aged, as if these people where chronologically older. As noted above, though, certain physiological differences between old skin and photoaged skin are apparent when histology and similarly direct measurements of the skin are taken.
It can be seen that the art has concentrated on preventing and repairing perceived damage to skin that appears aged because of chronic UV exposure. Sunscreens can prevent erythema, and this is generally considered sufficient for protection from the sun. The aforementioned patents teach treating photodamaged skin (although our patent defines photodamage by the presence of elevated MMPs, whereas Kligman's patent defines photodamage by clinical appearance).
Heretofore, nothing in the art has appeared to address what effect, if any, exposure to sunlight, and particularly the UV portion of the sun's spectrum, has on the production of collagen. Collagen is a polypeptide represented by the repeating peptides [-X-Y-Gly-]n where Gly is glycine and X and Y are other amino acids. About 20% of the remaining amino acids are an equal amount of proline and 4-hydroxyproline; analysis for hydroxyproline, because it is an unusual amino acid, is one method for assaying collagen or procollagen amounts. Collagen also contains other unusual amino acids, such as 3-hydroxyproline and hydroxylysine. Nineteen different types of collagen have been identified. Collagen Types I (85+%) and III (8+%) are the predominant types of collagen in human skin and are present as fibrils. Structurally, three collagen polypeptides wrap around each other in a helix to form a triple helix collagen molecule. These molecules are packed in a five-stranded rope-like structure wherein each collagen molecule is quarter-staggered with respect to the next to form a microfibril. Microfibrils are subsequently wrapped around other microfibrils to form fibrils, which in turn wrap around other fibrils to produce even larger fibers. The production of collagen fibers in vivo requires activation of the collagen biosynthesis pathway by which transcription in the cell nucleus promotes polypeptide synthesis via translation from mRNA, organization of the polypeptides into a procollagen triple helix in the cytoplasm, secretion of procollagen from the cell, and then cleavage reactions, fibril assembly, and cross-linking extracellularly. Unlike many proteins that are stored in secretory granules and then secreted from the cell upon demand, collagen is secreted continuously. According to Goldsmith, op. cit. (at 492), not only do retinoic acid, glucocorticoids, and vitamin D3 derivatives all decrease collagen synthesis, but so do other retinoids.